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Potential Achilles heels of SARS-CoV-2 are best displayed by the base order-dependent component of RNA folding energy.

ABSTRACT: The base order-dependent component of folding energy has revealed a highly conserved region in HIV-1 genomes that associates with RNA structure. This corresponds to a packaging signal that is recognized by the nucleocapsid domain of the Gag polyprotein. Long viewed as a potential HIV-1 "Achilles heel," the signal can be targeted by a new antiviral compound. Although SARS-CoV-2 differs in many respects from HIV-1, the same technology displays regions with a high base order-dependent folding energy component, which are also highly conserved. This indicates structural invariance (SI) sustained by natural selection. While the regions are often also protein-encoding (e. g. NSP3, ORF3a), we suggest that their nucleic acid level functions can be considered potential "Achilles heels" for SARS-CoV-2, perhaps susceptible to therapies like those envisaged for AIDS. The ribosomal frameshifting element scored well, but higher SI scores were obtained in other regions, including those encoding NSP13 and the nucleocapsid (N) protein.

SUBMITTER: Zhang C

PROVIDER: S-EPMC8410225 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Shorter heels are linked with greater elastic energy storage in the Achilles tendon.

Project description:Previous research suggests that the moment arm of the m. triceps surae tendon (i.e., Achilles tendon), is positively correlated with the energetic cost of running. This relationship is derived from a model which predicts that shorter ankle moment arms place larger loads on the Achilles tendon, which should result in a greater amount of elastic energy storage and return. However, previous research has not empirically tested this assumed relationship. We test this hypothesis using an inverse dynamics approach in human subjects (n = 24) at speeds ranging from walking to sprinting. The spring function of the Achilles tendon was evaluated using specific net work, a metric of mechanical energy production versus absorption at a limb joint. We also combined kinematic and morphological data to directly estimate tendon stress and elastic energy storage. We find that moment arm length significantly determines the spring-like behavior of the Achilles tendon, as well as estimates of mass-specific tendon stress and elastic energy storage at running and sprinting speeds. Our results provide support for the relationship between short Achilles tendon moment arms and increased elastic energy storage, providing an empirical mechanical rationale for previous studies demonstrating a relationship between calcaneal length and running economy. We also demonstrate that speed and kinematics moderate tendon performance, suggesting a complex relationship between lower limb geometry and foot strike pattern.

| S-EPMC8087768 | biostudies-literature

Achilles Heels of Senescent Cells: From Transcriptome to Senolytic Drugs

2015-03-10 | GSE66236 | GEO

Achilles Heels of Senescent Cells: From Transcriptome to Senolytic Drugs

Project description:The healthspan of mice is enhanced by selectively killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and burden of age-related chronic diseases. As senescent cells resist apoptosis, we used microarrays to identify transcripts and pathways that differ between senescent and non-senescent preadipocytes, and might be involved in resistance to apoptosis. Primary human abdominal subcutaneous preadipocytes were isolated from 8 healthy lean kidney donors. All subjects were matched by age,gender and BMI. The protocol was approved by the Mayo Clinic Foundation Institutional Review Board for Human Research. Preadipocytes were radiated at 10 Gy to induce senescence or were sham-radiated. From senescent cells RNA was isolated 20 days after irradiation.

2015-03-10 | E-GEOD-66236 | biostudies-arrayexpress

SynLeGG: analysis and visualization of multiomics data for discovery of cancer 'Achilles Heels' and gene function relationships.

Project description:Achilles' heel relationships arise when the status of one gene exposes a cell's vulnerability to perturbation of a second gene, such as chemical inhibition, providing therapeutic opportunities for precision oncology. SynLeGG (www.overton-lab.uk/synlegg) identifies and visualizes mutually exclusive loss signatures in 'omics data to enable discovery of genetic dependency relationships (GDRs) across 783 cancer cell lines and 30 tissues. While there is significant focus on genetic approaches, transcriptome data has advantages for investigation of GDRs and remains relatively underexplored. SynLeGG depends upon the MultiSEp algorithm for unsupervised assignment of cell lines into gene expression clusters, which provide the basis for analysis of CRISPR scores and mutational status in order to propose candidate GDRs. Benchmarking against SynLethDB demonstrates favourable performance for MultiSEp against competing approaches, finding significantly higher area under the Receiver Operator Characteristic curve and between 2.8-fold to 8.5-fold greater coverage. In addition to pan-cancer analysis, SynLeGG offers investigation of tissue-specific GDRs and recovers established relationships, including synthetic lethality for SMARCA2 with SMARCA4. Proteomics, Gene Ontology, protein-protein interactions and paralogue information are provided to assist interpretation and candidate drug target prioritization. SynLeGG predictions are significantly enriched in dependencies validated by a recently published CRISPR screen.

| S-EPMC8265155 | biostudies-literature

Role of the closing base pair for d(GCA) hairpin stability: free energy analysis and folding simulations.

Project description:Hairpin loops belong to the most important structural motifs in folded nucleic acids. The d(GNA) sequence in DNA can form very stable trinucleotide hairpin loops depending, however, strongly on the closing base pair. Replica-exchange molecular dynamics (REMD) were employed to study hairpin folding of two DNA sequences, d(gcGCAgc) and d(cgGCAcg), with the same central loop motif but different closing base pairs starting from single-stranded structures. In both cases, conformations of the most populated conformational cluster at the lowest temperature showed close agreement with available experimental structures. For the loop sequence with the less stable G:C closing base pair, an alternative loop topology accumulated as second most populated conformational state indicating a possible loop structural heterogeneity. Comparative-free energy simulations on induced loop unfolding indicated higher stability of the loop with a C:G closing base pair by ~3 kcal mol(-1) (compared to a G:C closing base pair) in very good agreement with experiment. The comparative energetic analysis of sampled unfolded, intermediate and folded conformational states identified electrostatic and packing interactions as the main contributions to the closing base pair dependence of the d(GCA) loop stability.

| S-EPMC3201870 | biostudies-literature

Nucleosome spacing and chromatin higher-order folding.

Project description:Packing of about two meters of the human genome DNA into chromatin occupying a several micron-sized cell nucleus requires a high degree of compaction in a manner that allows the information encoded on DNA to remain easily accessible. This packing is mediated by repeated coiling of DNA double helix around histones to form nucleosome arrays that are further folded into higher-order structures. Relatively straight DNA linkers separate the nucleosomes and the spacing between consecutive nucleosome varies between different cells and between different chromosomal loci. In a recent work ( 1) our group used a biochemically defined in vitro reconstituted system to explore how do various DNA linkers mediate nucleosome array packing into higher-order chromatin structures. For long nucleosome linkers (about 60 bp) we observed a more open chromatin structure and no effect of small linker length alterations (±2-4 bp) on chromatin folding. In striking contrast, for shorter linkers (20-32 bp) we found more compact packing with strong periodical dependence upon the linker DNA lengths. Our data together with high-resolution nucleosome position mapping provide evidence for the natural nucleosome repeats to support a chromatin architecture that, by default, restricts spontaneous folding of nucleosome arrays into compact chromatin fibers. We suggest that incomplete folding of the nucleosome arrays may promote global inter-array interactions that lead to chromatin condensation in metaphase chromosomes and heterochromatin.

| S-EPMC3515531 | biostudies-literature

Achilles' Heel of SARS-CoV-2 Structure.

Project description:Guided by evolutionarily signaled vulnerabilities in the structure of SARS-CoV-2, we identify epitopes in free monomers of the spike protein that steer the generation of induced or administered antibodies geared at promoting destabilization of the virus quaternary structure, thereby hampering infectivity.

| S-EPMC7552172 | biostudies-literature

Examining a Thermodynamic Order Parameter of Protein Folding.

Project description:Dimensionality reduction with a suitable choice of order parameters or reaction coordinates is commonly used for analyzing high-dimensional time-series data generated by atomistic biomolecular simulations. So far, geometric order parameters, such as the root mean square deviation, fraction of native amino acid contacts, and collective coordinates that best characterize rare or large conformational transitions, have been prevailing in protein folding studies. Here, we show that the solvent-averaged effective energy, which is a thermodynamic quantity but unambiguously defined for individual protein conformations, serves as a good order parameter of protein folding. This is illustrated through the application to the folding-unfolding simulation trajectory of villin headpiece subdomain. We rationalize the suitability of the effective energy as an order parameter by the funneledness of the underlying protein free energy landscape. We also demonstrate that an improved conformational space discretization is achieved by incorporating the effective energy. The most distinctive feature of this thermodynamic order parameter is that it works in pointing to near-native folded structures even when the knowledge of the native structure is lacking, and the use of the effective energy will also find applications in combination with methods of protein structure prediction.

| S-EPMC5940758 | biostudies-literature

Principal component analysis for protein folding dynamics.

Project description:Protein folding is considered here by studying the dynamics of the folding of the triple beta-strand WW domain from the Formin-binding protein 28. Starting from the unfolded state and ending either in the native or nonnative conformational states, trajectories are generated with the coarse-grained united residue (UNRES) force field. The effectiveness of principal components analysis (PCA), an already established mathematical technique for finding global, correlated motions in atomic simulations of proteins, is evaluated here for coarse-grained trajectories. The problems related to PCA and their solutions are discussed. The folding and nonfolding of proteins are examined with free-energy landscapes. Detailed analyses of many folding and nonfolding trajectories at different temperatures show that PCA is very efficient for characterizing the general folding and nonfolding features of proteins. It is shown that the first principal component captures and describes in detail the dynamics of a system. Anomalous diffusion in the folding/nonfolding dynamics is examined by the mean-square displacement (MSD) and the fractional diffusion and fractional kinetic equations. The collisionless (or ballistic) behavior of a polypeptide undergoing Brownian motion along the first few principal components is accounted for.

| S-EPMC2652707 | biostudies-literature

Last-come, best served? Mosquito biting order and Plasmodium transmission.

Project description:A pervasive characteristic of parasite infections is their tendency to be overdispersed. Understanding the mechanisms underlying this overdispersed distribution is of key importance as it may impact the transmission dynamics of the pathogen. Although multiple factors ranging from environmental stochasticity to inter-individual heterogeneity may explain parasite overdispersion, parasite infection is also overdispersed in an inbred host population maintained under laboratory conditions, suggesting that other mechanisms are at play. Here, we show that the aggregated distribution of malaria parasites within mosquito vectors is partially explained by a temporal heterogeneity in parasite infectivity triggered by the bites of mosquitoes. Parasite transmission tripled between the mosquito's first and last blood feed in a period of only 3 h. Surprisingly, the increase in transmission is not associated with an increase in parasite investment in production of the transmissible stage. Overall, we highlight that Plasmodium is capable of responding to the bites of mosquitoes to increase its own transmission at a much faster pace than initially thought and that this is partly responsible for overdispersed distribution of infection. We discuss the underlying mechanisms as well as the broader implications of this plastic response for the epidemiology of malaria.

| S-EPMC7739503 | biostudies-literature

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